The Action Potential

1 STAR TREK:TNG “Another Piece of the Action” by John Erik Ege EHP EXPERIMENTAL HOME PUBLISHING “Another Piece of the Action” edition 4, Nov 30th 2008 (edition 3, September 29th 2007, second edition was June 2007, and the first edition Feb 2006) EPH Copyright 2007 All Rights Reserved. Licensing for this is pending and can only be considered fan fiction at this time. The author agrees to share this edition for the sake of editing purposes with the understanding that Paramount, the official owners of Star Trek related products, may revoke the sharing privilege. Comments and corrections can be directed to the author for story refinement. Author contact info: John Erik Ege 214 907 4070 Email solarchariot@hotmail.com For this edition I would like to thank Mike Eden and Doctor Porter for their assistance in editing, providing comments, and all our dialogues of all things Trek. Their support, compliments, and criticism have helped me to stay focus on this project. with love, always john erik “Another Piece of the Action” is book two in a completed trilogy. Editing versions of book one, “A Touch of Greatness,” book three- “Both Hands Full,” and book four- “Necessary Evil,” may be attained by contacting the author. 2 PROLOGUE Tammas Parkin Arblaster-Garcia closed his eyes. He noted the time on his chronometer, provided by his neural implant, and ran some quick calculations. Admiral Leonard H McCoy would be dead just over seven hours now, which meant he had a window of about thirty more minutes in which he could still use the Kelvan technology to resuscitate and restore him to perfect health. The Kelvan ship was in the hangar bay and the control interface he required was in lock down. The technology was basically a computer console woven into a cloth bracelet. The bracelet’s fabric was a metallic-gold color which highlighted the only other noticeable feature, the silver button. When touched, the button became a conductor of a sort, connecting the computer to the nerves in the fingertip and from there establishing a direct connection to the brain of the user. An intellectual component was necessary to access the computer, a threshold below which one couldn’t access it at all. The minimum intellectual component might establish a connection but that person risked permanent brain damage. The person with sufficient intellectual capacity could access the computer and do miracles. Garcia met and exceeded this attribute, and it was not due to genetic manipulation, good luck, good nutrition, or even a proper education. He was Kelvan, not by birth, but by design. He was descendant from humans who were once Kelvan, and in an attempt to make him more Kelvan than human his neural structure had been modified. The neural map for the Kelvan physiology had been impressed on top of his human neural structure over a period of time starting from conception and ending five years after he was born in a series of procedures, each one building on the previous session’s work. The procedures hadn’t been perfect, but it had sufficiently changed his psyche so that he could, through the use of Kelvan technology similar to a transporter, be converted into a Kelvan. The final The Action Potential The Action Potential Bởi: OpenStaxCollege The functions of the nervous system—sensation, integration, and response—depend on the functions of the neurons underlying these pathways To understand how neurons are able to communicate, it is necessary to describe the role of an excitable membrane in generating these signals The basis of this communication is the action potential, which demonstrates how changes in the membrane can constitute a signal Looking at the way these signals work in more variable circumstances involves a look at graded potentials, which will be covered in the next section Electrically Active Cell Membranes Most cells in the body make use of charged particles, ions, to build up a charge across the cell membrane Previously, this was shown to be a part of how muscle cells work For skeletal muscles to contract, based on excitation–contraction coupling, requires input from a neuron Both of the cells make use of the cell membrane to regulate ion movement between the extracellular fluid and cytosol As you learned in the chapter on cells, the cell membrane is primarily responsible for regulating what can cross the membrane and what stays on only one side The cell membrane is a phospholipid bilayer, so only substances that can pass directly through the hydrophobic core can diffuse through unaided Charged particles, which are hydrophilic by definition, cannot pass through the cell membrane without assistance ([link]) Transmembrane proteins, specifically channel proteins, make this possible Several channels, as well as specialized energy dependent “ion-pumps,” are necessary to generate a transmembrane potential and to generate an action potential Of special interest is the carrier protein referred to as the sodium/potassium pump that moves sodium ions (Na+) out of a cell and potassium ions (K+) into a cell, thus regulating ion concentration on both sides of the cell membrane 1/15 The Action Potential Cell Membrane and Transmembrane Proteins The cell membrane is composed of a phospholipid bilayer and has many transmembrane proteins, including different types of channel proteins that serve as ion channels The sodium/potassium pump requires energy in the form of adenosine triphosphate (ATP), so it is also referred to as an ATPase As was explained in the cell chapter, the concentration of Na+ is higher outside the cell than inside, and the concentration of K+ is higher inside the cell is higher than outside That means that this pump is moving the ions against the concentration gradients for sodium and potassium, which is why it requires energy In fact, the pump basically maintains those concentration gradients Ion channels are pores that allow specific charged particles to cross the membrane in response to an existing concentration gradient Proteins are capable of spanning the cell membrane, including its hydrophobic core, and can interact with the charge of ions because of the varied properties of amino acids found within specific domains or regions of the protein channel Hydrophobic amino acids are found in the domains that are apposed to the hydrocarbon tails of the phospholipids Hydrophilic amino acids are exposed to the fluid environments of the extracellular fluid and cytosol Additionally, the ions will interact with the hydrophilic amino acids, which will be selective for the charge of the ion Channels for cations (positive ions) will have negatively charged side chains in the pore Channels for anions (negative ions) will have positively charged side chains in the pore This is called electrochemical exclusion, meaning that the channel pore is charge-specific Ions can also be specified by the diameter of the pore The distance between the amino acids will be specific for the diameter of the ion when it dissociates from the water molecules surrounding it Because of the surrounding water molecules, larger pores are not ideal for smaller ions because the water molecules will interact, by hydrogen bonds, more readily than the amino acid side chains This is called size exclusion Some ion channels are selective for charge but not necessarily for size, and thus are called a 2/15 The Action Potential nonspecific channel These nonspecific channels allow cations—particularly Na+, K+, and Ca2+—to cross the membrane, but exclude anions Ion channels not always freely allow ions to diffuse across the membrane They are opened by certain events, meaning the channels are gated So another way that channels can be categorized is on the basis of how they are gated Although these classes of ion channels are found primarily in cells of nervous or muscular tissue, they also can be found in cells of epithelial and connective tissues A ligand-gated channel opens because a signaling molecule, a ligand, binds to the extracellular region of the channel This type of channel is also known as an ionotropic receptor because when the ligand, known as a neurotransmitter in the nervous system, binds to the ... P1: JRQ-IZZ-KDD/kaa P2: JzL 0521829496c13.xml CY335B/Dembski 0 521 82949 6 March 10, 2004 2:25 13 The Inbuilt Potentiality of Creation John Polkinghorne Our understanding of the very early universe tells us that we live in a world that seems to have originated some fourteen billion years ago from a very simple state. The small, hot, almost uniform expanding ball of energy that is the cosmologist’s picture of the universe a fraction of a second after the Big Bang has turned into a world of rich and diversified complexity – the home of saints and scientists. Although, as far as we know, carbon-based life appeared only after about ten billion years of cosmic history, and self- conscious life after fourteen billion years, there is a real sense in which the universe was pregnant with life from the earliest epoch. anthropic fine-tuning One can say this because, although the actual realisation of life has pro- ceeded through an evolutionary process with many contingent features (the role of “chance”), it has also unfolded in an environment of lawful regularity of a very particular kind (the role of “necessity”). The so-called Anthropic Principle (Barrow and Tipler 1986; Leslie 1989) refers to a collection of scientific insights that indicate that necessity had to take a very specific form if carbon-based life were ever to be a cosmic possibility. In other words, it would not have been enough to have rolled the evolutionary dice a suffi- cient number of times for life to have developed somewhere in the universe. The physical rules of the cosmic game being played also had to take a very precise form if biology were to be a realisable possibility. The given physi- cal fabric of the world had to be endowed with anthropic potentiality from the start. It is worth recalling some of the many considerations that have led to this conclusion. A good place to begin is by asking where carbon itself, along with the nearly thirty other elements also necessary for life, comes from. Because the very early universe was so simple, it only made very simple things. Three minutes after the hectic events of the immediate post–Big Bang era, the 246 P1: JRQ-IZZ-KDD/kaa P2: JzL 0521829496c13.xml CY335B/Dembski 0 521 82949 6 March 10, 2004 2:25 The Inbuilt Potentiality of Creation 247 universe settled down into a state in which its matter was three-quarters hydrogen and one-quarter helium. These are the simplest of the chemical elements; on their own, they have too boring a chemistry to be the basis for complex and interesting developments. It was only when the nuclear furnaces of the first generation of stars started up, a billion years or so after the Big Bang, that richer possibilities began to be realised. Every atom of carbon in our bodies was once inside a star – we are people of stardust. One of the great successes of twentieth-century astrophysics was to unravel the chain of processes by which the chemical elements were made, within stars and in the death throes of supernova explosions. As an example, consider how carbon was formed. The first stars con- tained α-particles, the nuclei of helium. To make carbon, three α-particles must combine to yield carbon 12. One might suppose that the natural way to achieve this would be via the intermediate state of a berylium nucleus (made of two αs), to which a third α might subsequently become attached; but this possibility is made problematic by the extreme instability RESEARCH ARTICLE Open Access Acute nerve stretch and the compound motor action potential Mark M Stecker * , Kelly Baylor, Jacob Wolfe and Matthew Stevenson Abstract In this paper, the acute changes in the compound motor action potential (CMAP) during mechanical stretch were studied in hamster sciatic nerve and compared to the changes that occur during compression. In response to stretch, the nerve physically broke when a mean force of 331 gm (3.3 N) was applied while the CMAP disappeared at an average stretch force of 73 gm (0.73 N). There were 5 primary measures of the CMAP used to describe the changes during the experiment: the normalized peak to peak amplitude, the normalized area under the curve (AUC), the normalized duration, the normalized velocity and the normalized velocity corrected for the additional path length the impulses travel when the nerve is stretched. Each of these measures was shown to contain information not available in the others. During stretch, the earliest change is a reduction in conduction velocity followed at higher stretch forces by declines in the amplitude of the CMAP. This is associated with the appearance of spontaneous EMG activity. With stretch forces < 40 gm (0.40 N), there is evidence of increased excitability since the corrected velocities increase above baseline values. In addition, there is a remarkable increase in the peak to peak amplitude of the CMAP after recovery from stretch < 40 gm, often to 20% above baseline. Multiple means of predicting when a change in the CMAP suggests a significant stretch are discussed and it is clear that a multifactorial approach using both velocity and amplitude parameters is important. In the case of pure compression, it is only the amplitude of the CMAP that is critical in predicting which changes in the CMAP are associated with significant compression. Background In a previous paper [1], the response of the compound motor action potential (CMAP) produced by peripheral nerve stimulation was studied during a pure compres- sion injury of the nerve. Although, this is one mechan- ismbywhichanervemightbeinjuredduringsurgery, nerves can also be in jured as a co nseque nce of stretch. In order to use the CMAP as a means of warning a sur- geon that a nerve is undergoing significant stretch dur- ing a surgical procedure a number of criteria must be met. First, those characteristics of the CMAP that can be measured in real time must be identified and their changes during stretch must be understood. Second, optimal means of classifying whether there is impending injury to the nerve based upon these parameters must be found. Finally, the sensitivity and specificity of these changes in predicting injury must be determined. These are the primary goals of this paper. It is well known that stretching a periphe ral nerve can cause injury. Many studies have demonstrated that stretch can damage the myelin [2-4]as well as the cytos- keleton [5,6]. The neurophysiology of stretch injury has also been investigated but primaril y in regar d to the sub- acute injury caused b y limb lengthening [7-10] rather than the acute injury that may occur during a surgical procedure. In particular, the electrophysiologic character- istics of these subacute injuries may be quite different from acute injuries especially since it has been shown that longitudinal stretching of the nerve for prolonged periods is associated with a greater chanc e of injury at the same stretching force [11] than a brief period of stretch. Electrophysiologic studies of stretch have show n both reductions in conduction velocity and decreased CMAP amplitudes but have not evaluated the criteria that could be used to determine which electrophysiologic * Correspondence: mmstecker@gmail.com Department of Neuroscience, Marshall University School of Medicine, Huntington, WV 25701 USA Stecker et al. Journal of Brachial Plexus and Peripheral Nerve Injury 2011, 6:4 http://www.jbppni.com/content/6/1/4 JOURNAL OF BioMed Central Page 1 of 7 (page number not for citation purposes) Theoretical Biology and Medical Modelling Open Access Research Repolarization of the action potential enabled by Na + channel deactivation in PSpice simulation of cardiac muscle propagation Lakshminarayanan Ramasamy 1 and Nicholas Sperelakis* 2 Address: 1 Dept. of Electrical Computer Engineering and Computer Science, University of Cincinnati College of Engineering, Cincinnati, OH 45219, USA and 2 Dept. of Molecular & Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0576, USA Email: Lakshminarayanan Ramasamy - laksnarayana@yahoo.com; Nicholas Sperelakis* - spereln@ucmail.uc.edu * Corresponding author Abstract Background: In previous studies on propagation of simulated action potentials (APs) in cardiac muscle using PSpice modeling, we reported that a second black-box (BB) could not be inserted into the K + leg of the basic membrane unit because that caused the PSpice program to become very unstable. Therefore, only the rising phase of the APs could be simulated. This restriction was acceptable since only the mechanism of transmission of excitation from one cell to the next was being investigated. Methods and results: We have now been able to repolarize the AP by inserting a second BB into the Na + leg of the basic units. This second BB effectively mimicked deactivation of the Na + channel conductance. This produced repolarization of the AP, not by activation of K + conductance, but by deactivation of the Na + conductance. The propagation of complete APs was studied in a chain (strand) of 10 cardiac muscle cells, in which various numbers of gap-junction (gj) channels (assumed to be 100 pS each) were inserted across the cell junctions. The shunt resistance across the junctions produced by the gj-channels (R gj ) was varied from 100,000 M? (0 gj-channels) to 10,000 M? (1 gj-channel), to 1,000 M? (10 channels), to 100 M? (100 channels), and 10 M? (1000 channels). The velocity of propagation (θ, in cm/s) was calculated from the measured total propagation time (TPT, the time difference between when the AP rising phase of the first cell and the last cell crossed -20 mV, assuming a cell length of 150 µm. When there were no gj-channels, or only a few, the transmission of excitation between cells was produced by the electric field (EF), i.e. the negative junctional cleft potential, that is generated in the narrow junctional clefts (e.g. 100 A) when the prejunctional membrane fires an AP. When there were many gj-channels (e.g. 1000 or 10,000), the transmission of excitation was produced by local-circuit current flow from one cell to the next through the gj-channels. Conclusion: We have now been able to simulate complete APs in cardiac muscle cells that could propagate along a single chain of 10 cells, even when there were no gj-channels between the cells. Background There are no low-resistance connections between the cells in several different cardiac muscle and smooth muscle preparations [1-3]. In a computer simulation study of propagation in cardiac muscle, it was shown that the elec- tric field (EF) generated in the narrow junctional clefts Published: 12 December 2005 Theoretical Biology and Medical Modelling 2005, 2:48 doi:10.1186/1742-4682-2-48 Received: 08 November 2005 Accepted: 12 December 2005 This article is available from: http://www.tbiomed.com/content/2/1/48 © 2005 Ramasamy and Sperelakis; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Theoretical Biology and Medical Modelling 2005, 2:48 http://www.tbiomed.com/content/2/1/48 Page 2 of 7 (page number not for citation purposes) when the prejunctional membrane fires an action poten- tial (AP) depolarizes INVESTIGATIONS INTO THE CHEMOPREVENTIVE POTENTIAL OF STILBENES, INDOLINONES AND ISOINDIGOS: SYNTHESIS AND MODE OF ACTION STUDIES ZHANG WEI (B.Sc., SOOCHOW UNIVERSITY) NATIONAL UNIVERSITY OF SINGAPORE 2008 INVESTIGATIONS INTO THE CHEMOPREVENTIVE POTENTIAL OF STILBENES, INDOLINONES AND ISOINDIGOS: SYNTHESIS AND MODE OF ACTION STUDIES ZHANG WEI (B.Sc., SOOCHOW UNIVERSITY) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACY NATIONAL UNIVERSITY OF SINGAPORE 2008 Acknowledgements With my deepest gratitude and delight, I would like to dedicate my acknowledgment to my supervisor, Assoc. Professor Go Mei Lin for her constant encouragement and guidance. Without her consistent and illuminating instruction, this thesis could not have reached its present form. Secondly, I would like to thank Professor Loh Teck Peng and his postgraduate students Zhao Yu Jun and Shen Zhi Liang for invaluable discussions and suggestions for organic synthesis. I want to thank Oh Tang Booy and Ng Sek Eng for providing technical assistance. Thirdly, I would like to thank all technical and research staffs in department of pharmacy for their help and support. In addition, I want to thank all postgraduate students and FYP students in Medicinal Chemistry Research Lab, Liu Xiao Ling, Lee Chong Yew, Leow Jo Lene, Sim Hong May, Nguyen Thi Hanh Thuy, Wee Xi Kai, Wee Kiang Yeo, Liu Jian Chao, Tee Hui Wearn and Suresh Kumar Gorla. Many thanks to my friends Reng Yu Peng, Chen Wei Qiang, Li Cheng, Ling Hui, Wang Chun Xia. I am gratefully acknowlege the research scholarship from National University of Singapore. Last but not least, my thanks would go to my beloved family for their loving considerations and great confidence in me all through these years. I wish to give special thanks to my wife Liu Xiao Hong for her consistent encouragement and support, to allow me to finish this thesis. I Table of Contents Acknowledgements I  Table of Contents II  Publications and Conferences VI  Summary . VII  Chapter Introduction . 1  1.1.  Chemoprevention of Cancer . 1  1.2.  Potential Mechanisms of Chemoprevention 3  1.3. Induction of NQO1 as a Chemopreventive Strategy 4  1.4.  Regulation of NQO1 by the ARE/XRE and Keap1/Nrf2/ARE Pathways . 6  1.5.  Monofunctional and Bifunctional Inducers of Phase II Enzymes 7  1.6.  Stilbenes as Lead Structures for Chemopreventive Activity . 9  1.7.  Statement of Purpose 11  Chapter Design and Synthesis of Target Compounds 16  2.1.  Introduction 16  2.2.  Methoxystilbenes . 16  2.2.1  Rationale of drug design . 16  2.2.2. Chemical considerations 18  2.2.3.  Assignment of configuration . 23  2.2.4.  Experimental methods 24  2.3.  3-Substituted Indolin-2-ones 29  2.3.1.  Rationale of drug design . 29  2.3.2.  Chemical considerations . 33  2.3.3.  Assignment of configuration . 39  2.3.4.  Experimental methods 44  II 2.4.  Summary 47  Chapter Induction of NQO1 Activity by Methoxystilbenes . 48  3.1.  Introduction ... event—it either happens or it does not If the threshold is not reached, then no action potential occurs If depolarization reaches -55 mV, then the action potential continues and runs all the way... after hyperpolarization Propagation of the Action Potential The action potential is initiated at the beginning of the axon, at what is called the initial segment There is a high density of voltage-gated... “released” when you push a button 7/15 The Action Potential Graph of Action Potential Plotting voltage measured across the cell membrane against time, the action potential begins with depolarization,